development of the endocrine system prof. dr. olcay evliyaoğlu


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DEVELOPMENT OF THE ENDOCRINE SYSTEM Prof. Dr. Olcay Evliyaolu Slide 2 Steroid hormones: are not stored rate of synthesis = rate of secretion Slide 3 Adrenal, gonadal steroids: Synthesis is controlled by trophic hormones. Stimulating hormone -------> receptor --------> activation of adenylate cyclase ------> cAMP increases Slide 4 McCune Albright Syndrome: Activating mutation in the alpha subunit of G protein. Testotoxicosis: Activating mutation of LH receptor ( transmembrane domain - interaction with G protein.) Slide 5 Disorders of hormone resistance Insulin resistance Testicular feminization Certain types of dwarfism Diabeted insipidus (nephrogenic) Pseudohypoparathyroidism Slide 6 Hormone --> receptor number decreases down regulation or desensitization obesity - insulin precocious puberty - GnRH analogues Slide 7 Hormone --> receptor number increases up regulation estrogen - FSH ---> LH receptors increase Slide 8 Distinguishing characteristic of endocrine systems: feedback control & hormone production. Slide 9 The paradigm for feedback control is the interaction of the pituitary gland with the thyroid, adrenals and gonads. Hormones produced in peripheral endocrine organs feedback on the hypothalamic-pituitary system ------> regulate the production of the trophic hormones that control peripheral endocrine glands. Slide 10 Negative Feedback Metabolite Cortisol --> ACTH/ CRH Thyroid hormones --> TSH /TRH Slide 11 Short Feedback TSH --> TRH ACTH --> CRH Slide 12 Positive Feedback Hypophysogonadal (only example) : Estrogen --> LH, FSH Slide 13 Adrenal gland develpment Embryology Mesoderm........adrenal cortex Ectoderm.........adrenal medulla 5-6 wk fetal adrenal cortex Outer definitive zone (glucokortikoids and mineralocorticoids) Inner fetal zone (androgenic precursors) Slide 14 At birth AG is 0,5 % of total BW Glomerulosa 15 % Fasiculata 75 % Reticularis 10 % Slide 15 Fetal zone disappears around 1 years of age Glomerularis and fasiculata development is completed in 3 years. Reticularis development is completed in 15 years Slide 16 Fetal cortisol --> cortisone (Midgestation: cortisone (x4-5 cortisol)) Cortisone: relatively inactive glucocorticoid; it protects the anabolic milieu of the fetus: cortisol can retard placental and fetal growth. As term approaches; liver, lung express 11-beta hydroxy steroid dehydrogenase I activity: cortisone --> cortisol Cortisol: an important stimulus for preparing the fetus for extrauterine survival. Slide 17 Development of pituitary gland Slide 18 Slide 19 Growth hormone The most produced hormone in the pituitary. Single chain alpha-helical nonglukolized polypeptide. Consists of 191 aminoacids and two intramolecular disulfide bounding. 22kDa molecler weight 75% 20kDa 10-25% N-asetile ve desamine forms veya oligomers Slide 20 GH GH-BHBP Extracellular part of GH rec Slide 21 Growth hormone Encoded by GH-1 gene. Locolized on 17q 22-24 chromosome. Slide 22 GH secretion Under control of 2 hypothalamic hormones Growth hormone releasing hormone(GHRH) Somatotropin release-inhibiting factor (SRIF, somatostatin) Slide 23 GHRH Protein with 44 aminoacids Vazoactive intestinal polypeptide/ glukagon family Slide 24 GH secretion Slide 25 Human growth hormone (hGH) Nonpulsatile GH secretion in infants. During childhood 24 hour integrated GH secretion increase progressively. In puberty GH secretion amplitude increase to peak levels ( effect of gonadal steroids on GHRH). GH secretion decrease with age but secreted life long. Slide 26 GH-releasing peptides (GHRP)or secretagogues (GHS) Ligands that increase GH produced by humans Do not use GHRH or SRIF receptors GHS-R G-protein associated rec protein kinase C hypothalamus, pituitary somatotrophs Slide 27 Ghrelin Endogen ligand for GHS-R. Increase GH secretion in rats (intracellular Ca increase). Physiologic mediator of nutrition Slide 28 GH effect Bound to GH-binding protein (GHBP) (at least 50 %) GHBP, is the extra cellular component of GH-R Slide 29 GH-R member of cytokine rec family 620 aa protein On plasma membrane. Extracellular part is transport protein Single transmembrans helix Intracellular part Slide 30 GH IGFs (somatomedins) Similliar to proinsuline Effect on extrauterine growth via IGF-1ile (70aa polypeptide) Slide 31 Disorders associated with low IGF-1 levels GH deficiency Hypothyroidism Malnutrition Chronic diseases Slide 32 Fetal IGF-1 is correlated with gestastional age Newborn IGF-1 levels are 30-50 % of adult values Increase through out childhood and reach adult levels in puberty Gonadal steroids increase IGF-1 production. In puberty levels are 2-3 fold higher than adult values Increase osteoblastic activity and collagen synthesis stimulate long bone growth Slide 33 IGF s are bound to IGF binding proteins (IGFBP) t Transport to target tissue. Modulate the relation with IGF rec 6 different IGFBP are cloned IGFBP-3, 90 % related to GH Slide 34 IGF-1 rec Structure resembles insulin rec (2 alpha,2beta subunits) Slide 35 GH increase GHRH Arginin,leucine Alpha adrenergic agonists (alpha 2 adrenergic) Beta adrenergic antagonists Dopamine, acetylcholine Hypoglycemia Sleeping Exercise Slide 36 GH decrease Hypergylcemia Obesity ncrease in free FA Glucocortikoid excess Hypothyroidism Incresed adrenergic tonus Psychosocial deprivition Slide 37 Slide 38 Slide 39 Slide 40 Is derived from primitive pharynx-precursor of T4 producing cells And fourth pharengeal pouch- precursor of calcitonin(C) cells For development and descent of thyroid several transcription factors such asTITF1/NKX2, FOXE1 and PAX 8 are needed to work on time and coordinated Thyroid gland development Slide 41 Embryogenesis After 1st month it is visable. At ntrauterin 8 wk Tg synthesis begins shows thyroid activity 10. wk iodine trapping 12. wk colloid formation begins and withTSH sec from pituitary T4 synthesis begins This synthesis increase progresively with hypothalamic maturation after 18 wk of gestation Slide 42 Tiroid kolloidi tiroglobulin Protein sentezi ekirdek DNA/RNA sentezi Damar G proteini Thyroid hormone biosynthesis Slide 43 Thyroid hormone synthesis Uptake I uptake actively with Na-iodine pump Slide 44 Thyroid hormone synthesis Organification yodine + thyroglobulin MIT DIT Slide 45 Thyroid hormone synthesis Conjugation MIT + DIT T3 DIT +DITT4 Thyroid peroksidase(TPO) Slide 46 TROKSN (T4) I HO I 1 2 3 4 56 O I I 1 2 3 4 56 CH 2 CH COOH NH 2 (fenol halkas)(tirozil halkas) b a I R O I I R I R O I I R 5 - monodeyidinasyon5 - monodeyidinasyon Tip I-II monodeyiodinaz Tip III monodeyiodinaz T3 rT3 Slide 47 Serum thyroid hormone concentrations TT3 TBG TT4 rT3/T4 Slide 48 Effects of thyroid hormones Growth O2 usage Heat production Nerve functions Lipids Proteins Nucleic acids Vitamins Inorganic ions Other hormones Effect metabolism Slide 49 Actions of thyroid hormones Slide 50 Regulation of thyroid hormones Slide 51 CAMP Iodine uptake odothyrosine synthesis Tg synthesis Glucose oxidation Colloid pinositosis Hormone secretion Thyroid growth ATP Adenilate cyclase TSH G Protein Slide 52 Regulation of thyroid hormones Iodine intake Physiologic limits Thyroid membrane iyodine uptake Pharmachologic doses TPO activity Iodine organification (Wolf Chaikoff effect) TSH induced CAMP stimulation inhibitted Tg synthesis Hormone secretion Thyroid growth - - - - Slide 53 Iodine needs in different times of age Age and stages of life Daily idoine recommendation( g) 6